Cardiomyopathy is a serious heart disease that often leads to congestive heart failure, a condition in which the heart muscle can no longer effectively pump blood. Patients that suffer from various muscle diseases, including Duchenne muscular dystrophy (DMD), develop progressive cardiomyopathy. Cellular cardiomyoplasty (CCM), a procedure that involves the transplantation of exogenous cells into damaged myocardium, has been proposed as a possible therapy to regenerate diseased myocardium and deliver therapeutic genes. Although a wide variety of cell types has been used for CCM, various limitations (including ethical, biological, or technical challenges) have impeded their suitability for use in human patients. We recently have used the modified preplate technique to isolate a novel population of muscle-derived stem cells (MDSCs) that display improved transplantation capacity in skeletal muscle when compared to satellite cells. The MDSCs' ability to proliferate in vivo for an extended period of time-- combined with their strong capacity for serf-renewal, multipotent differentiation, and immune-privileged behavior--reveals, at least in part, a basis for the benefits associated with their use in cell transplantation in skeletal muscle. The proposed project will investigate the use of MDSCs as a novel cell source for cardiac cell transplantation in a cardiomyopathic murine model of muscular dystrophy. We already have observed that MDSCs delivered by intra-cardiac injection display good cell survival and can deliver dystrophin within the dystrophic myocardium. In this project we will investigate whether MDSCs implanted in the hearts of dystrophic mdx mice display an improved transplantation capacity when compared to conventional satellite cell implantation (Aim #1). We then will explore the relative contribution of the MDSCs' capacity for long-term proliferation and self-renewal (Aim #2) to the increased regenerative capacity of these cells after transplantation in heart muscle. Finally, we will determine the degree to which development of approaches to prevent fibrosis (Aim #3) and improve angiogenesis (Aim #4) would further enhance the regenerative capacity of muscle-derived cells in the heart. This project will increase our understanding of the basic biology of myogenic cell populations that display stem cell characteristics. This information may, in turn, unveil new techniques to improve heart regeneration and repair via the transplantation of muscle-derived stem cells.